Specific Aims The goals of this project are to identify genetic variants that predispose to thrombotic microangiopathies and validate them via functional studies. The initial focus will be on mutations in the complement and clotting systems in patients with atypical hemolytic uremic syndrome (aHUS), thrombotic thrombocytopenic purpura (TTP) and, especially, the pregnancy related disorder preeclampsia (PE). The strategic approach will center on next generation sequencing, specifically targeted deep resequencing and exomic sequencing of TMA patient cohorts. To tackle this project, we will take advantage of the considerable expertise in genomics at Washington University as well as senior investigators with much know-how in defining the functional implications of mutants in these two great serine protease pathways of human plasma that protect us from bleeding and infections.